Method of treatment

ABSTRACT

The invention provides the use of darifenacin, or a pharmaceutically acceptable derivative thereof, in the manufacture of a medicament for the reduction of urgency in patients suffering from overactive bladder.

CROSS REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of U.S. ProvisionalApplication No. 60/347,456 filed Jan. 11, 2002, and U.K. ProvisionalApplication No. 0129962.7 filed Dec. 14, 2001.

[0002] This invention relates to a new use of darifenacin, and itspharmaceutically acceptable derivatives.

[0003] Darifenacin is(S)-2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-diphenyl-acetamideand is disclosed in European Patent No 0388054, Examples 1B and 8. It isreferred to therein as3-(S)-(−)-(1-carbamoyl-1,1-diphenylmethyl)-1-[2-(2,3-dihydro-benzofuran-5-yl)ethyl]pyrrolidine.It is indicated in the treatment of urinary incontinence and irritablebowel syndrome and has the following structure:

[0004] The symptoms of overactive bladder (OAB) include urinaryfrequency and urgency, with or without incontinence in the absence oflocal pathological or systemic condition. Urgency is described in thedraft ICS Terminology Report [Terminology Report of the InternationalContinence Society; Draft 6, Aug. 15, 2001] as the sudden compellingdesire to pass urine, which is difficult to control.

[0005] Recently, the terms OAB Wet and OAB Dry have been proposed todescribe OAB patients with or without incontinence respectively. Overallprevalence of OAB Wet and Dry is similar in men and women with aprevalence rate in the US of 16.6% [Stewart et al, Prevalence ofOveractive Bladder in the United States: Results from the NOBLE Program;Abstract Presented at the 2^(nd) International Consultation onIncontinence, July 2001, Paris, France]. Until recently, the cardinalsymptom of OAB was believed to be incontinence. However, with the adventof the new terms this is clearly not meaningful for the large number ofsufferers who are not incontinent (i.e. OAB Dry patients). Thus, arecent study from Liberman et al [Health Related Quality of Life AmongAdults with Symptoms of Overactive Bladder: Results From A USCommunity-Based Survey; Urology 57(6), 1044-1050, 2001] examined theimpact of all OAB symptoms on the quality of life of a community-basedsample of the US population. This study demonstrated that individualssuffering from OAB without any demonstrable loss of urine have animpaired quality of life when compared with controls. Additionally,individuals with urgency alone have an impaired quality of life comparedwith controls.

[0006] Thus, urgency is now believed to be the primary symptom of OAB,but to date it has not been evaluated in a quantified way in clinicalstudies.

[0007] It has now been found that darifenacin, and its pharmaceuticallyacceptable derivatives, is useful in the reduction of urgency inpatients suffering from overactive bladder.

[0008] This finding is surprising because it could not have beenpredicted that a compound known to be useful in the treatment ofincontinence (i.e. the unwanted and often unconscious leaking of urine)would be able to reduce the feeling of urgency (i.e. the suddencompelling desire to pass urine). It is even more surprising thatdarifenacin, and its pharmaceutically acceptable derivatives, is able toreduce the feeling of urgency in patients who are not incontinent (i.e.OAB Dry patients).

[0009] Thus, according to the present invention, there is provided theuse of darifenacin, or a pharmaceutically acceptable derivative thereof,in the manufacture of a medicament for the reduction of urgency inpatients suffering from overactive bladder (OAB).

[0010] Pharmaceutically acceptable derivatives of darifenacin includesolvates and salts, particularly acid addition salts such as thehydrobromide salt.

[0011] The patients to be treated may be suffering from wet overactivebladder (OAB Wet) or dry overactive bladder (OAB Dry). The darifenacin,or a pharmaceutically acceptable derivative thereof, can be administeredalone or in any convenient pharmaceutical presentation, including thosementioned in European Patent No 388054. Oral administration ispreferred. In the present indication, a suitable dosage of darifenacin,or of the active darifenacin moiety in a pharmaceutically acceptablederivative thereof, for a 70 kg person, is in the range 3.75-40 mgdaily, for example 7.5-30 mg daily. The dosage may be administered in,say, 3 divided doses or in a single controlled release formulation.

[0012] However, it is preferred that the darifenacin, or apharmaceutically acceptable derivative thereof, is administered in adosage form that is adapted to release at least 10% of the darifenacin,or a pharmaceutically acceptable derivative thereof, in the lowergastrointestinal tract of the patient. Such formulations are describedin U.S. Pat. No. 6,106,864 (the teaching of which is incorporated hereinby reference). The preferred such formulation is a slow release matrixtablet (see particularly Example 3 of U.S. Pat. No. 6,106,864).

[0013] The invention further provides darifenacin, or a pharmaceuticallyacceptable derivative thereof, for use in the reduction of urgency inpatients suffering from overactive bladder.

[0014] The invention further provides a method of reducing urgency inpatients suffering from overactive bladder, which comprisesadministering darifenacin, or a pharmaceutically acceptable derivativethereof, to a patient in need of such treatment.

[0015] The invention is illustrated by the following examples.

EXAMPLES

[0016] Clinical Investigations of Urgency in Subjects with OveractiveBladder

[0017] Two novel methods for the assessment of urgency were used. Thefirst was for use in a large scale clinical trial, and the second wasfor use in clinical laboratory studies.

[0018] In both of these studies, darifenacin was administered as itshydrobromide salt. It was presented in slow release matrix tablets ofthe type described in U.S. Pat. No. 6,106,864, particularly Example 3.Tablets were administered once daily (o.d.).

[0019] Clinical Study 1

[0020] In this study, OAB Wet patients recorded each episode of urgencyper day and the overall severity of urgency for each day in a diary. Theseverity of urgency was recorded by the use of a visual analogue scale(VAS) where the anchor points were mild and severe.

[0021] Darifenacin (as hydrobromide salt; 7.5 mg, 15 mg and 30 mg of theactive moiety, o.d.) and placebo were evaluated in subjects with adiagnosis of overactive bladder in a multicentre trial and symptoms ofurgency were assessed using the VAS at baseline and at the end of thestudy (12 weeks of treatment).

[0022] 108 patients (14 male, 94 female) received 7.5 mg; 107 patients(15 male, 92 female) received 15 mg; 114 patients (16 male, 98 female)received 30 mg; and 108 patients (18 male, 90 female) received placebo.

[0023] Results

[0024] Darifenacin (7.5-30 mg) produced a dose-related reduction in boththe number of episodes of urgency and the overall severity of urgencyexperienced by the OAB subject in the clinical study. The effect wassignificantly greater than that produced by placebo. The data ispresented below in Table 1 and 2. TABLE 1 Effect of Darifenacin andPlacebo on Frequency and Severity of Urgency in OAB Subjects Placebo 7.5mg 15 mg 30 mg No of episodes of urgency/day Baseline 8.1 8.5    8.6 8.4 Median change from −1.2 −1 .8  −2.3*  −3*** baseline Median %Change from −15.7 −29.2 −26.9 −33.1 baseline Severity of urgency/dayBaseline 53.5 53.2   56.2  53.5 Median change from −3.9 −7  −7*  −9.4*baseline

[0025] TABLE 2 Effect of Darifenacin on Frequency & Severity of Urgencyin OAB subjects corrected for placebo 7.5 mg 15 mg 30 mg No of episodesof urgency/day Baseline 8.5  8.6  8.4 Median difference from −0.5 −1.1*−1.4*** placebo Severity of urgency/day Baseline 53.2 56.2 53.5 Mediandifference from −2.5 −3.8* −5.5* placebo

[0026] Clinical Study 2

[0027] This study used a novel method for measuring the time between thefirst onset of the urgency and the need to micturate, which is known asthe ‘warning time’. A modified stop-watch was used which required thesubject to press a button at the onset of urge and a second button whenthey felt they needed to micturate. Darifenacin (as the hydrobromidesalt; 30 mg o.d.) and placebo were evaluated in subjects with symptomsof urgency. The subjects were a mixture of OAB Wet and OAB Drysufferers. The ‘warning time’ was assessed at baseline and following 2weeks of treatment using the modified stop watch.

[0028] 36 patients (29 female, 7 male) received darifenacin; and 36patients (22 female, 14 male) received placebo.

[0029] Results

[0030] Treatment with darifenacin of subjects with urgency produced asignificant increase in the warning time when compared with subjectstreated with placebo. The data are displayed in Table 3.

[0031] It should be noted that both OAB Wet and OAB Dry subjectsresponded to treatment. TABLE 3 Effect of Darifenacin and Placebo onWarning Time in Subjects with Urgency and Frequency Warning Time (Min)Darifenacin Placebo Baseline (Median) 4.7 9.4 Week 2 (Median)  8.4** 4.1

[0032] Median difference from placebo 4.3 minutes

[0033] Conclusions

[0034] The results show darifenacin produced a clinically significantattenuation of the symptom of urgency in subjects with overactivebladder.

1. The use of darifenacin, or a pharmaceutically acceptable derivativethereof, in the manufacture of a medicament for the reduction of urgencyin patients suffering from overactive bladder.
 2. The use as claimed inclaim 1, wherein the darifenacin is in the form of a pharmaceuticallyacceptable acid addition salt.
 3. The use as claimed in claim 1, whereinthe darifenacin is in the form of its hydrobromide salt.
 4. The use asclaimed in any one of the preceding claims, wherein the patients to betreated are suffering from wet overactive bladder.
 5. The method in anyone of claims 1 to 3, wherein the patients to be treated are sufferingfrom dry overactive bladder.
 6. The use as claimed in any one of thepreceding claims, wherein the darifenacin, or a pharmaceuticallyacceptable derivative thereof, is administered in a dosage form that isadapted to release at least 10% of said darifenacin, or apharmaceutically acceptable derivative thereof, in the lowergastrointestinal tract of the patients.
 7. The use as claimed in claim6, wherein the dosage form is a slow release matrix tablet. 8.Darifenacin, or a pharmaceutically acceptable derivative thereof, foruse in the reduction of urgency in patients suffering from overactivebladder.
 9. A method of reducing urgency in patients suffering fromoveractive bladder, which comprises administering darifenacin, or apharmaceutically acceptable derivative thereof, to a patient in need ofsuch treatment.